puc-header

Amyloid Oligomers of Mutant p53 in Living Cells Result in Oncogenic Gain of Function in Glioblastoma

61 Pages Posted: 5 Sep 2019 Publication Status: Published

See all articles by Murilo M. Pedrote

Murilo M. Pedrote

Universidade Federal do Rio de Janeiro (UFRJ) - Programa de Biologia Estrutural

Michelle F. Motta

Universidade Federal do Rio de Janeiro (UFRJ) - Programa de Biologia Estrutural

Douglas R. Norberto

Federal University of ABC Region

Tania C. L. S. Spohr

Instituto Estadual do Cérebro Paulo Niemeyer (IECPN)

Flavia R. S. Lima

Universidade Federal do Rio de Janeiro (UFRJ)

Enrico Gratton

University of California, Irvine - Laboratory for Fluorescence Dynamics (LFD)

Jerson Silva

Universidade Federal do Rio de Janeiro (UFRJ) - Programa de Biologia Estrutural

Guilherme A. P. de Oliveira

Universidade Federal do Rio de Janeiro (UFRJ) - Programa de Biologia Estrutural

More...

Abstract

Tumor-associated p53 mutations endow cells with malignant phenotypes, including chemoresistance to standard treatments. Amyloid-like oligomeric species of mutant p53 have been attributed to transformation of the p53 tumor suppressor into an oncogene. However, the composition and distribution of mutant p53 oligomers linked to a chemoresistance phenotype are unknown. Knowledge of the mechanism involved in the conversion of p53 is also sparse. Here, we report the massive accumulation of a p53 mutant within amyloid-like p53 oligomers in brain cells from glioblastoma tumors leading into chemoresistance gain of function. This finding, along with statistical analysis of data from fluorescence fluctuation spectroscopy, pressure-induced measurements, and thioflavin T kinetics, demonstrates the distribution of oligomers larger than the active tetrameric form of p53 in the nuclei of living cells and the destabilization of native-drifted p53 species that become amyloid. Collectively, these results suggest the role of amyloid-like mutant p53 oligomers as participants in the chemoresistance phenotype of malignant and invasive brain tumors and shed light on new therapeutic options to avert cancer.

Suggested Citation

Pedrote, Murilo M. and Motta, Michelle F. and Norberto, Douglas R. and Spohr, Tania C. L. S. and Lima, Flavia R. S. and Gratton, Enrico and Silva, Jerson and de Oliveira, Guilherme A. P., Amyloid Oligomers of Mutant p53 in Living Cells Result in Oncogenic Gain of Function in Glioblastoma (August 31, 2019). Available at SSRN: https://ssrn.com/abstract=3445669 or http://dx.doi.org/10.2139/ssrn.3445669
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Murilo M. Pedrote

Universidade Federal do Rio de Janeiro (UFRJ) - Programa de Biologia Estrutural ( email )

Brazil

Michelle F. Motta

Universidade Federal do Rio de Janeiro (UFRJ) - Programa de Biologia Estrutural ( email )

Brazil

Douglas R. Norberto

Federal University of ABC Region ( email )

Rua Santa Adélia, 166
Bloco Delta, 3rd Floor, Room 304
São Paulo, Santo André 09210-170
Brazil

Tania C. L. S. Spohr

Instituto Estadual do Cérebro Paulo Niemeyer (IECPN) ( email )

Brazil

Flavia R. S. Lima

Universidade Federal do Rio de Janeiro (UFRJ) ( email )

Av; Pasteur, 250
terreo - Bairro Maracana
Rio de Janeiro, Rio de Janeiro 23890000
Brazil

Enrico Gratton

University of California, Irvine - Laboratory for Fluorescence Dynamics (LFD) ( email )

3208 Natural Sciences II
Irvine, CA 92697‑2715
United States

Jerson Silva (Contact Author)

Universidade Federal do Rio de Janeiro (UFRJ) - Programa de Biologia Estrutural ( email )

Brazil

Guilherme A. P. De Oliveira

Universidade Federal do Rio de Janeiro (UFRJ) - Programa de Biologia Estrutural

Brazil

Click here to go to Cell.com

Paper statistics

Abstract Views
295
Downloads
10
PlumX Metrics